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Abstract

Cocaine sensitization is associated with cocaine-induced hyperexcitability of pyramidal projection neurons within the medial prefrontal cortex (mPFC). Such hyperexcitability presumably results in increased glutamatergic input to reward-affiliated brain regions such as the ventral tegemental area (VTA) and nucleus accumbens (NAc), consequently facilitating drugseeking behavior. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in cocaine addiction and demonstrated to increase neuronal excitability, therefore, the aim of the present study was to investigate the effect of intra-mPFC mGluR5 manipulation on behavioral and neurochemical sensitization and drug-seeking. Bilateral cannulae were implanted into the mPFC of male Sprague-Dawley rats and mGluR5 antagonist MTEP (15 nmol/side) or saline was microinjected into the region five minutes prior to a challenge cocaine injection. Our data showed that intra-mPFC mGluR5 blockade via MTEP prevented late, but not early, behavioral sensitization. Further, intra-mPFC mGluR5 activation via DHPG (30 uM) increased mPFC and NAc glutamate levels in sensitized animals during early and late withdrawal, respectively. Finally, we observed a nonsignificant trend toward an MTEP-induced reduction in drug-seeking following the presentation of a cocaine-associated cue in animals that had been trained to selfadminister cocaine. Taken together, our data suggest mPFC mGluR5 plays a role in cocaine addiction, possibly through the modulation of mPFC pyramidal neuronal excitability